Curare formulas

Full understanding is hampered by current deficiencies in our knowledge of the chemical composition of the plants concerned—for tubocurarine has so far only been found in Chondrodendron tomentosum—yet, as demonstrated by the curare formulas given in Section 1.2.3.1, there are curares from regions 2 and 3 that do not have this species as an ingredient, so that their muscle-relaxant activity must be due to alkaloids from other plants, e.g. Abuta (cf. Section 1.4.6.4) or Cur area species. 

Curare was first examined by Roulin and Boussingalt, who isolated a syrupy body, which they named curarine much later a similar substance was obtained by Buchner, - and in 1865 Preyer announced that he had obtained curarine and its salts in a well-crystallised condition, and by analysis of the platinichloride, ascertained its composition to be C10H35N. Sachs - was only able to obtain an amorphous alkaloid, to which he assigned the formula CigHjjN. The work of Boehm explained to some extent these discrepant results he examined all three varieties and showed that they differed in composition, and that the isolation of the various curarines as single substances required special processes. 

Alkaloids of Goukd ok Calabash Curare. The toxic constituent of this form, as prepared by Boehm, was an amorphous curarine to which the formula C gHjgONj was assigned. Gourd curare has been investigated in recent years by Wieland et aZ. and by Schmid and Karrer. ... 

While these experiments stimulated other research, it is sad to relate that the proposed explanation is not correct. It required almost seventy years, however, before it was realized that the curare-like action of the onium salts was a result of their ionic character. Other examples of the role of spatial arrangement were discovered. For example, quoting Stewart Ishizuka (1897) found that maleic acid was a much stronger poison than its stereoisomer, fumaric acid 1.94 grammes for every kilogramme in a dog s weight was a fatal dose of the former acid, while the same dose of fumaric acid was harmless. Similarly these isomers were found to have differential effects on microorganisms. Stewart also rationalized the mydriatic action of tropine and the inactivity of pseudotropine in terms of three-dimensional formulae as shown below (1 and 2). In many ways, these structural representations are close to the present-day conformational structures (pseudotropine = 3, tropine = 4) ... 

Indeed, all the calabash curare alkaloids with high curarizing activity are now known to possess C40 molecules. The converse, however, is not true, for caracurine V dimethochloride (Section III, C) has the molecular formula yet has a surprisingly low physio-... 

Still less was known about toxiferine I at this time. Because of strong similarities between the properties of toxiferine I and those of curare alkaloids with established C40 molecular formulas, the earlier formulas were tentatively revised to C4oH46-48N202 + (82). Toxiferine I dichloride has [a]D — 540° (in water) and the picrate has mp 278°-280° (dec.). 

This pale-yellow quaternary alkaloid, picrate mp 189°, [a]D of chloride — 930° (in water), was first isolated from a calabash curare (12) it was subsequently isolated from other calabash curare preparations (34, 35) and has been identified chromatographically in extracts from the bark of S. mitscherlichii (33) and other Strychnos species (7). The identification of C-fluorocurarine is greatly helped by its deep-blue fluorescence in UV-light. Analyses of the crystalline iodide and anthraquinone sulfonate showed its molecular formula to be C2oH23N20+ (12), which is in agreement with all subsequent work. The properties of C-fluorocurarine, particularly its low toxicity and high Rc values, suggest that it is a C20 alkaloid rather than a double molecule. This was confirmed (102) by application of the partial quaternization method to one of its derivatives (see subsequent discussion) the method cannot be applied to C-fluorocurarine itself, since on pyrolysis it is not smoothly demethylated to the... 

The quaternary C-alkaloid D was first isolated (16) from a sample of calabash curare and was later encountered (24) as one of the products formed when C-dihydrotoxiferine I is treated with dilute acid in the presence of oxygen. Because of its low mobility on paper chromatograms, it was considered to be a dimeric alkaloid, and the formula C4oH48N4Or was proposed (116) on the basis of analyses of the several crystalline salts afforded by this alkaloid. Despite its bisquaternary nature, C-alkaloid D has a low curarizing activity, and in this respect it is similar to caracurine V dimethochloride mentioned earlier. C-Alkaloid D chloride shows [a]D — 51° (in 1 1 aqueous acetone). 

Some of the most difficult structural problems in the indole alkaloid field are associated with the bisindole alkaloids of the vobtusine type. Since 1955, vobtusine has been isolated on numerous occasions, often in large quantities, from the Apocynaceae species Callichilia, Conopharyngia, Rejoua, and Voacanga A correct molecular formula could only be determined by high-resolution mass spectrometry. In 1966 a partial structure was proposed for the alkaloid and later in the same year a complete structure was put forward. An unambiguous structural proof is, however, still lacking. The difficulty arises from the complete resistance of the alkaloid and its derivatives to cleavage, in contrast, for example, to the dimers of the voacamine and vinblastine types. Non-cleavable dimers occur also in calabash-curare but in these cases chemical correlation with cleavable alkaloids has been possible (see Section 2, p. 209). To date no bisindole alkaloid related to vobtusine has been found which can be split into monomeric units. 

In searching for possible useful curarizing agents as well as for clues to the structures of the calabash and toxiferine alkaloids, a number of quaternary salts of open and closed carboline-type compounds have been examined. Some of these compounds which are possible open-chain fragments of the toxiferines, are indicated by formulas IX-XVIII. 

These degradation reactions thus established the chemical constitution of the alkaloid as l-(4-hydroxybenzyl)-6-methoxy-7-hydroxy-l, 2,3,4-tetra-hydroisoquinoline (LXXXIII). It is of interest that this formula, if quatemized, expresses closely one-half of the structure of the curare alkaloid d-tubocurarine chloride. A suitably bisected formula of this drug is shown in LXXXIV. 

Lycopodine. Formula see Lycopodium alkaloids. CifiHjjNO, Mr 247.38, mp. 116°C, [d -24.5° (C2H5OH). A Lycopodium alkaloid of the C. N type from many club moss species (Lycopodiaceae). It is the most widely distributed Lycopodium alkaloid and usually occurs as the major alkaloid. It was first isolated over 100 years ago from a clubmoss species. L. is toxic and exerts a curare-like paralysing activity. Several syntheses have been reported. ... 

During their ethnobotanical researches. Prance and his coworkers (66, 171) have noted the ingredients of the curares prepared by a number of tribes about whom there has so far been little information. Two of the formulas they were able to acquire are given below. The bulleted plant names have been kindly supplied by Prof. Prance. 

As is evident from the above formulas, besides the essential components, a variety of other plants may be added during the preparation of the poison. Material of species from well over 60 genera are known to have been included as ingredients in curare formulations the Kofan Indians of Colombia/ Ecuador, for example, have utilized more than 75 species in making their various arrow and dart poisons (172). These plant additives, many of which are not known to contain any obviously toxic substances, may be included for a variety of reasons to thicken or harden the extract and enable it to adhere to the dart or arrow or to reinforce the effects of the poison or for... 

---